CN100439370C

CN100439370C - Trifluoromethylpurines as phosphodiesterase 4 inhibitors

Info

Publication number: CN100439370C
Application number: CNB02807890XA
Authority: CN
Inventors: 刘瑞平; 汉斯-于尔根·厄恩斯特·埃斯; 艾伦·霍珀; 荣雅晶; 阿肖克·泰姆
Original assignee: Memory Pharmaceuticals Corp
Current assignee: Memory Pharmaceuticals Corp
Priority date: 2001-02-08
Filing date: 2002-02-08
Publication date: 2008-12-03
Anticipated expiration: 2022-02-08
Also published as: MXPA03007134A; CA2438099A1; WO2002098878A1; EP1383767A1; US20030045533A1; CN1501927A; US20040242598A1; AU2002313673B2; KR100863622B1; KR20040008127A; US20080119495A1; BR0207302A; HK1066546A1; US7342021B2; JP4443215B2; US20100010020A1; JP2004528391A

Abstract

PDE4 inhibition is achieved by novel compounds of the Formula I: wherein R<1 >and R<2 >are as defined herein.

Description

Trifluoromethylpurines as phosphodiesterase 4 inhibitors

This application claims priority from U.S. provisional application 60/267,195 filed on 8/2/2001 and U.S. provisional application 60/344,824 filed on 7/1/2002.

Technical Field

The present invention relates generally to the field of phosphodiesterase 4(PDE4) enzyme inhibition. More particularly, the invention relates to selective PDE4 inhibition by novel adenine analogs, methods for preparing these compounds, compositions containing these compounds, and methods of use thereof.

Background

Cyclic nucleotide specific Phosphodiesterases (PDEs) represent a class of enzymes that catalyze the hydrolysis of various cyclic nucleosides monophosphate, including cAMP and cGMP. These cyclic nucleotides function as second messengers within the cell and as messengers carry impulses from cell surface receptors that have bound various hormones and neurotransmitters. PDEs function to regulate the levels of cyclic nucleotides in cells and maintain cyclic nucleotide homeostasis by degrading these single cyclic nucleotides, resulting in the termination of their messenger role.

PDE enzymes can be classified into 11 classes based on their specificity for hydrolysis of cAMP or cGMP, their sensitivity to calcium, calmodulin or cGMP modulation, and their selective inhibition by various compounds. For example, PDE1 is subject to Ca²⁺Calponin stimulation. PDE2 is cGMP-dependent and is found in the heart and adrenal glands. PDE3 is cGMP-dependent, and inhibition of this enzyme produces positive inotropic activity. PDE4 is cAMP specific and its inhibition results in airway relaxation, anti-inflammatory and antidepressant activity. PDE5 appears to be important in regulating cGMP levels in vascular smooth muscle, and thus PDE5 inhibitors may have cardiovascular activity. Because of their unique biochemical properties, PDEs are likely to undergo many different forms of regulation.

PDE4 differs in various kinetic properties, including low mie constants for cAMP and sensitivity to certain drugs. The PDE4 enzyme class consists of four genes that produce 4 isoforms of the PDE4 enzyme known as PDE4A, PDE4B, PDE4C and PDE4D [ see: wang et al, Expression, Purification, and charateristicionof human cAMP-Specific phosphorus estiferase (PDE4) Subtypes A, B, C, and D, biochem. Biophys. Res. Comm., 234, 320-324 (1997). In addition, various splice variants of each PDE4 isoform have been identified.

The PDE4 isoenzyme is located in the cytosol of cells and is not associated with any known membrane structure. The PDE4 isozyme specifically inactivates cAMP by catalyzing its hydrolysis to adenosine 5' -monophosphate (AMP). Modulation of cAMP activity is important in many biological processes, including inflammation and memory. PDE4 isoenzyme inhibitors such as rolipram, pyraclostrobin, CDP-840 and ariflo are potent anti-inflammatory agents and may therefore be used in the treatment of diseases where inflammation is an issue such as asthma or arthritis. Furthermore, rolipram improves cognitive ability in rats and mice in a learning model.

Rolipram piclamilast

In addition to these compounds such as rolipram, xanthine derivatives such as pentoxifylline, denbufylline and theophylline inhibit PDE4 and have recently attracted considerable attention for their cognition enhancing effects. cAMP and cGMP are second messengers that regulate cellular responses to many different hormones and neurotransmitters. Thus, PDE inhibition and the resultant increase in intracellular cAMP or cGMP in critical cells, such as those in the nervous system and other parts of the body, may be therapeutically important.

Rolipram, which was developed in the past as an antidepressant, selectively inhibits the PDE4 enzyme and has become a standard agent for the classification of PDE enzyme subtypes. Early work in The area Of PDE4 focused on depression and inflammation, and subsequently has extended to indications including, for example, dementia [ see "The PDE IV Family Of Calcium-phosphorus diesterases Enzymes", john a. lowe, III et al, Drugs Of The Future 1992, 17 (9): 799 overview 807 ]. Other clinical developments of rolipram and other first generation PDE4 inhibitors have been terminated by the side effects of these compounds. The major side effect in primates is emesis, while the major side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotropic effects, increased gastric acid secretion and gastric erosion.

Disclosure of Invention

The present invention relates to novel adenine compounds that inhibit the PDE4 enzyme, particularly with improved side effect profiles, such as being relatively non-emetic (e.g., as compared to the prior art compounds discussed above). In particular, the present invention relates to novel 9-substituted-2-trifluoromethyladenine compounds having PDE4 inhibitory activity. Preferably, the compound selectively inhibits the PDE4 enzyme. The compounds of the invention are also readily accessible to cells, particularly cells of the nervous system.

Furthermore, the present invention provides methods for the synthesis of compounds having such activity and selectivity, as well as methods for (and corresponding pharmaceutical compositions for) treating a patient, e.g., a mammal, including a human, in need of PDE inhibition, particularly PDE4 inhibition, a condition involving elevated intracellular levels of PDE4 or reduced levels of cAMP, e.g., involving neurological syndromes, particularly those associated with memory impairment, most particularly long-term memory impairment, wherein such memory impairment is due in part to catabolism of intracellular levels of cAMP by the PDE4 enzyme, or wherein such memory impairment may be ameliorated by effectively inhibiting PDE4 enzyme activity.

In a preferred aspect, the compounds of the invention ameliorate these disorders by inhibiting the PDE4 enzyme at doses that do not induce emesis.

Other aspects, objects, and advantages of the invention will be apparent to those skilled in the art upon further study of the specification and appended claims.

The present invention includes compounds of formula I:

wherein,

R¹is a compound of formula (I) in the formula (H),

an alkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy or combinations thereof, and wherein-CH₂The radical may optionally be replaced by-O-, -S-or-NH-;

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms;

R²is an alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy, cyano, or combinations thereof, wherein one or more-CH₂Each independently of the others, optionally substituted by-O-, -S-or-NH-, and wherein optionally one or more-CH₂CH₂The radicals-are in each case replaced by-CH-or-C.ident.C-,

alkyl ethers having 3 to 12 carbon atoms,

cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4Alkyl radical, C_1～4-alkoxy, cyano or a combination thereof,

cycloalkylalkyl having 4 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: c_1～4Alkyl, halo C_1～4Alkyl radical, C_1～4-alkoxy, cyano, halogen or combinations thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

arylalkyl having from 7 to 16 carbon atoms which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～ ₄Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1-4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

heteroarylalkyl wherein the heteroaryl moiety has 5 to 10 ring atoms, at least one of which is a heteroatom, and the alkyl moiety has 1 to 3 carbon atoms, the heteroaryl moiety being unsubstituted or substituted one or more times with: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

a heterocycle having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4-alkyl radicalHalogen substituted C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxyl, alkoxycarbonyl or combinations thereof (for example piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl and indolinyl),

heterocycle-alkyl wherein the heterocyclic moiety has 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, and the alkyl moiety has 1 to 3 carbon atoms, the heterocyclic moiety being non-aromatic and unsubstituted or substituted one or more times by: halogen, aryl, C_1～ ₄Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl or combinations thereof (for example piperidinyl-ethyl and pyrrolidinyl-methyl), or

A carbocycle, which is a non-aromatic, monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～ ₄-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof;

with the proviso that:

(a) when R is¹When it is methyl, R²Not being arylalkyl, heteroarylalkyl2- (1, 2, 3, 4-tetrahydro) quinolyl-methyl, methyl or 2-butyl;

(b) when R is¹When it is cyclopropyl, R²Is other than 4-methylbenzyl;

(c) when R is¹When it is ethyl, R²Is not ethyl, 3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl or 2-pyridylmethyl;

(d) when R is¹When it is cyclopropyl, R²Is not cyclopropylmethyl;

(e) when R is¹When is H, R²Is not methyl, ethyl, benzyl, 4-methylbenzyl or substituted tetrahydrofuranyl;

(f) when R is¹When it is methoxyethyl, R²Is not benzyl, 3-dimethylaminobenzyl or 3-thienylmethyl;

(g) when R is¹When it is isobutyl, R²Is not benzyl; and

(h) when R is¹When it is n-butyl, R²Is not n-butyl.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is methyl, R²Not being arylalkyl, heteroarylalkyl, 2- (1, 2, 3, 4-tetrahydro) quinolyl-methyl or C_1～5-an alkyl group.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is methyl, R²Not being arylalkyl, heteroarylalkyl, heterocycloalkyl or C_1～5-an alkyl group.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is cyclopropyl, R²Is not an arylalkyl group.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is ethyl, R²Not being arylalkyl, heteroarylalkyl or C_1～3-an alkyl group.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is cyclopropyl, R²Is not cycloalkylalkyl.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When is H, R²Not being arylalkyl, heterocyclic or C_1～3-an alkyl group.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is methoxyethyl, R²Is not arylalkyl or heteroarylalkyl.

According to a further aspect of the invention there is provided a class of compounds according to formula I wherein R is¹When it is butyl, R²Not being arylalkyl or C_1～5-an alkyl group.

According to a preferred aspect of the present invention there is provided a novel class of compounds according to formula II:

wherein

R¹' is methyl, ethyl or cyclopropyl; and

R²' is cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4Alkyl radical, C_1～4-alkoxy, cyano or a combination thereof,

heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

a heterocycle having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino, carboxy, alkoxycarbonyl or combinations thereof (such as piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl), or a carbocyclic ring which is a non-aromatic, monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～ ₄Alkyl, hydroxy, C_1～4Alkoxy, haloGeneration C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof.

According to another aspect of the present invention there is provided a novel class of compounds according to formula III:

wherein

R¹"is a radical of hydrogen or a radical of hydrogen,

an alkyl group having 1 to 5 carbon atoms,

an alkyl group having 1 to 5 carbon atoms, which is substituted one or more times with: halogen, hydroxy, oxygen, cyano, or combinations thereof,

a cycloalkyl group having 3 to 6 carbon atoms,

cycloalkyl having 3 to 6 carbon atoms, substituted one or more times with: halogen, alkyl, oxygen, or combinations thereof,

cycloalkylalkyl having 4 to 7 carbon atoms,

cycloalkylalkyl having 4 to 7 carbon atoms, substituted one or more times with:

C_1～4alkyl, halogen, halogeno C_1～4-an alkyl group or a combination thereof,

R²"is an alkyl group having 1 to 12 carbon atoms，

An alkyl group having 1 to 12 carbon atoms, which is substituted one or more times with: halogen, hydroxy, oxygen, cyano, or combinations thereof,

alkyl ethers having 3 to 12 carbon atoms,

a cycloalkyl group having 3 to 12 carbon atoms,

a cycloalkyl group having 3 to 12 carbon atoms, which is substituted one or more times with: halogen, C_1～4-an alkyl group, oxygen or a combination thereof,

cycloalkylalkyl having 4 to 12 carbon atoms,

cycloalkylalkyl having 4 to 12 carbon atoms, substituted one or more times with:

an aryl group having 6 to 10 carbon atoms,

an aryl group having 6 to 10 carbon atoms, which is substituted one or more times with: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxy alkoxy, carboxy, cyano, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

an arylalkyl group having 7 to 16 carbon atoms,

an arylalkyl group having 7 to 16 carbon atoms substituted one or more times with: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkanesOxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxy alkoxy, carboxy, cyano, C_2～4-acyl group, C_2～4Alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

a heteroaryl group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom,

substituted heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is substituted one or more times with: halogen, aryl, C_1～4Alkyl radical, C_1～ ₄Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-an alkylamino group or a combination thereof,

heteroarylalkyl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, or

Substituted heteroarylalkyl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, and which is substituted one or more times in the heteroaryl moiety by: halogen, aryl, C_1～4Alkyl radical, C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino or combinations thereof, and/or substituted in the alkyl moiety with halogen, oxygen, cyano or combinations thereof;

with the proviso that:

(a) when R is¹When "is methyl, R²"is not arylalkyl, heteroarylalkyl, methyl or 2-butyl,

(b) when R is¹When "is cyclopropyl, R²"is not a 4-methylbenzyl group,

(c) when R is¹When "is ethyl, R²"is not ethyl, and

(d) when R is¹When "is cyclopropyl, R²"is not cyclopropylmethyl.

According to a further aspect of the invention there is provided a class of compounds of formula III, wherein R¹"and R²"satisfies the following subformula:

IIIa R¹"is cyclopropyl; and

R²"is cycloalkyl.

IIIb R¹"is methyl; and

R²"is a cycloalkyl group.

IIIc R¹"is methyl, ethyl, cyclopropyl; and

R²"is phenyl or substituted phenyl.

IIId R¹"is methyl, ethyl, cyclopropyl; and

R²"is heteroaryl or substituted heteroaryl.

The compounds of the invention are effective in inhibiting or modulating PDE4 activity in an animal, such as a mammal, particularly a human. These compounds exhibit neurological activity, particularly when such activity affects cognition, including long-term memory. These compounds will also be effective in treating diseases involving reduced cAMP levels. This includes, but is not limited to, inflammatory diseases. These compounds may also be useful as antidepressants, or for the treatment of cognitive and adverse symptoms of schizophrenia.

The present invention provides, in a method aspect, a method for treating a patient (e.g., a mammal such as a human) suffering from a disorder (e.g., memory disorders, inflammatory diseases, depression, etc.) involving decreased cAMP levels and/or increased intracellular levels of PDE4, comprising administering to the patient a compound of formula Ia:

wherein,

R^1ais a compound of formula (I) in the formula (H),

an alkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy or combinations thereof, and wherein-CH₂The radical-may optionally be replaced by-O-, -S-or-NH-,

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms;

R^2ais an alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy, cyano, or combinations thereof, wherein one or more-CH₂Each independently of the others, optionally substituted by-O-, -S-or-NH-, and wherein optionally one or more-CH₂CH₂The radicals-are in each case replaced by-CH-or-C.ident.C-,

alkyl ethers having 3 to 12 carbon atoms,

heteroarylalkyl group wherein the heteroaryl moiety has 5 to 10 ringsWherein at least one ring atom is a heteroatom, and the alkyl moiety has 1 to 3 carbon atoms, and the heteroaryl moiety is unsubstituted or substituted one or more times with: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

a heterocycle having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxyl, alkoxycarbonyl or combinations thereof (for example piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl and indolinyl),

heterocycle-alkyl wherein the heterocyclic moiety has 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, and the alkyl moiety has 1 to 3 carbon atoms, the heterocyclic moiety being non-aromatic and unsubstituted or substituted one or more times by: halogen, aryl, C_1～ ₄Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl or combinations thereof (for example piperidinyl-ethyl and pyrrolinyl-methyl), or

A carbocycle which is a non-aromatic, monocyclic or bicyclic radical having 5 to 14 carbon atoms and which is unsubstituted or substitutedThe following groups are substituted one or more times: halogen, C_1～4Alkyl, halo C_1～ ₄-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof;

with the proviso that:

(a) when R is^1aWhen it is methyl, R^2aIs not arylalkyl, heteroarylalkyl, 2- (1, 2, 3, 4-tetrahydro) quinolyl-methyl, methyl or 2-butyl;

(b) when R is^1aWhen it is cyclopropyl, R^2aIs other than 4-methylbenzyl;

(c) when R is^1aWhen it is ethyl, R^2aIs not ethyl, 3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl or 2-pyridylmethyl;

(d) when R is^1aWhen it is cyclopropyl, R^2aIs not cyclopropylmethyl;

(e) when R is^1aWhen is H, R^2aIs not methyl, ethyl, benzyl, 4-methylbenzyl or substituted tetrahydrofuranyl;

(f) when R is^1aWhen it is methoxyethyl, R^2aIs not benzyl, 3-dimethylaminobenzyl or 3-thienylmethyl;

(g) when R is^1aWhen it is isobutyl, R^2aIs not benzyl; and

(h) when R is^1aWhen it is n-butyl, R^2aIs not n-butyl.

The invention is in the followingThe methods provide methods for treating a patient (e.g., a mammal such as a human) having a disorder (e.g., a memory disorder) involving a decrease in cAMP levels and/or an increase in intracellular PDE4 levels, comprising administering to the patient formula I^bAnd pharmaceutically acceptable salts thereof:

wherein,

R^1bis a compound of formula (I) in the formula (H),

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms;

R^2bis an alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy, cyano, or combinations thereof, wherein one or more-CH₂Each independently of the others, optionally substituted by-O-, -S-or-NH-, and wherein optionally one or more-CH₂CH₂The radicals-are in each case replaced by-CH-or-C.ident.C-,

alkyl ethers having 3 to 12 carbon atoms,

cycloalkylalkyl having 4 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: c_1～4-alkanesRadical, halo C_1～4Alkyl radical, C_1～4-alkoxy, cyano, halogen or combinations thereof,

heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkyl amino, carboxylAlkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

with the proviso that when R^1bWhen it is methyl, R^2bNot arylalkyl, methyl or 2-butyl, when R is^1bWhen is H, R^2bIs not benzyl.

In another method aspect, the invention provides a method for treating a patient (e.g., a mammal such as a human) suffering from a disorder (e.g., memory impairment) involving a decrease in cAMP levels and/or an increase in intracellular PDE4 levels, comprising administering to the patient formula I^cAnd pharmaceutically acceptable salts thereof:

wherein,

R^1cis a compound of formula (I) in the formula (H),

an alkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy or combinations thereof, and wherein-CH₂The radical may beOptionally replaced by-O-, -S-or-NH-,

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms;

R^2cis an alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy, cyano, or combinations thereof, wherein one or more-CH₂Each independently of the others, optionally substituted by-O-, -S-or-NH-, and wherein optionally one or more-CH₂CH₂The radicals-are in each case replaced by-CH-or-C.ident.C-,

alkyl ethers having 3 to 12 carbon atoms,

heteroarylalkyl wherein the heteroaryl moiety has 5 to 10 ring atoms, at least one of which is a heteroatom, and the alkyl moiety has 1 to 3 carbon atoms, the heteroaryl moiety being unsubstituted or substituted one or more times with: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-an alkylsulfinyl group,C_1～4-an alkylsulfonyl group or a combination thereof,

A carbocycle, which is a non-aromatic, monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～ ₄-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinylBase, C_1～4-alkylsulfonyl, phenoxy or combinations thereof;

with the proviso that the compound is not 6-methylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine.

In another method aspect, the invention provides a method for treating a patient (e.g., a mammal such as a human) suffering from a disorder (e.g., memory impairment) involving decreased cAMP levels and/or increased intracellular levels of PDE4, comprising administering to the patient a compound of formula II:

wherein

R¹' is methyl, ethyl or cyclopropyl; and

hetero ring having 5 to 10 ring atomsAryl, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

a heterocycle having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxyl, alkoxycarbonyl or combinations thereof (for example piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl and indolinyl), or

A carbocycle, which is a non-aromatic, monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～ ₄Alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof.

In another method aspect of the inventionMethods are provided for treating a patient (e.g., a mammal such as a human) having a disorder (e.g., memory impairment) involving reduced cAMP levels and/or increased intracellular PDE4 levels, comprising administering to the patient a compound of formula III^aAnd pharmaceutically acceptable salts thereof:

wherein,

R¹' is a hydrogen atom (H),

an alkyl group having 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy, oxygen, cyano, or combinations thereof,

cycloalkyl having 3 to 6 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, alkyl, oxygen or combinations thereof, or

Cycloalkylalkyl having 4 to 7 carbon atoms, which is unsubstituted or substituted one or more times by: c_1～4Alkyl, halogen, halogeno C_1～4-alkyl or combinations thereof; and

R²' is an alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, hydroxy, oxygen, cyano, or combinations thereof,

alkyl ethers having 3 to 12 carbon atoms,

cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4-an alkyl group, oxygen or a combination thereof,

cycloalkylalkyl having 4 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: c_1～4Alkyl, halogen, halogeno C_1～4-an alkyl group or a combination thereof,

aryl having 6 to 10 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxy alkoxy, carboxy, cyano, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

arylalkyl having from 7 to 16 carbon atoms which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxy alkoxy, carboxy, cyano, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, substituted one or more times with: halogen, aryl, C_1～4Alkyl radical, C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino or combinations thereof, or

Heteroarylalkyl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times in the heteroaryl part by: halogen, arylBase, C_1～4Alkyl radical, C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino or combinations thereof, and/or substituted in the alkyl moiety with halogen, oxygen, cyano or combinations thereof;

with the proviso that:

(a) when R is¹When'' is methyl, R²' "is not arylalkyl, heteroarylalkyl, methyl or 2-butyl.

In the formula III^aIn, R¹' preferably methyl, ethyl or cyclopropyl.

Assays for determining PDE inhibitory activity and selectivity for PDE4 inhibitory activity and selectivity for inhibiting the PDE4 isozyme are known in the art. See, for example, US6,136,821, the disclosure of which is incorporated herein by reference.

Herein, halogen means F, Cl, Br and I. Preferred halogens are F and Cl.

Alkyl, as a group or substituent per se or as part of a group or substituent (e.g. alkylamino, trialkylsiloxy, aminoalkyl, hydroxyalkyl) means a straight-chain or branched aliphatic hydrocarbon radical having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, in particular from 1 to 4 carbon atoms.

R¹The alkyl group of (A) has up to 5 carbon atoms, preferably 1 to 4 carbon atoms, especially 1 to 3 carbon atoms. Suitable R¹The alkyl group of (b) includes methyl, ethyl, propyl, isopropyl, butyl, isopropyl and pentyl. Suitable R¹Other examples of the alkyl group of (a) include a 1-, 2-or 3-methylbutyl group, a 1, 1-, 1, 2-or 2, 2-dimethylpropyl group and a 1-ethylpropyl group.

R²The alkyl group of (A) has up to 12 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable R²The alkyl group of (A) includes the above-listed R¹Alkyl groups of (A) and hexyl, heptyl,Octyl, nonyl, decyl, undecyl, dodecyl, 1-, 2-, 3-or 4-methylpentyl, tert-butyl, 1-, 1, 2-, 1, 3-, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.

Substituted alkyl is alkyl as described above, which is substituted in one or more positions with: halogen, oxygen, hydroxy, C_1～4-alkoxy, halo C_1～4-alkoxy and/or cyano. Halogen is a preferred substituent, particularly F and Cl.

Alkoxy means an alkyl-O-group in which the alkyl moiety is in accordance with the foregoing. Suitable alkoxy groups are methoxy, ethoxy, propoxy and butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and trifluoromethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl-O-CO-, wherein the alkyl moiety is in accordance with the foregoing. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl.

Alkenyl means a straight or branched aliphatic group containing 2 to 12 carbon atoms, wherein one or more-CH groups₂-CH₂Each-structure is replaced by-CH ═ CH-. Suitable alkenyl groups are vinyl, 1-propenyl, 2-methylvinyl, 1-butene, 2-butene, 1-pentenyl and 2-pentenyl.

Alkynyl means a straight or branched chain aliphatic radical containing 2 to 12 carbon atoms, wherein one or more-CH groups₂-CH₂-the structures are each replaced by-C ≡ C-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl and 2-butynyl.

Cycloalkyl means a monocyclic, bicyclic or tricyclic non-aromatic saturated hydrocarbon radical. R¹The cycloalkyl group of (A) has 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms, particularly 3 carbon atoms. Suitable R¹Cycloalkyl groups of (a) include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. R²The cycloalkyl group has 3 to 12 carbon atomsPreferably 3 to 10 carbon atoms, particularly 4 to 8 carbon atoms. Suitable R²The cycloalkyl group of (A) includes the above-listed R¹And cycloheptyl, cyclooctyl, cyclononyl, norbornyl, 1-decalin, adamantan-1-yl and adamantan-2-yl groups. R²Other suitable cycloalkyl groups of (a) include spiro [2, 4 ]]Heptyl, spiro [2, 5 ]]Octyl, bicyclo [5.1.0]Octyl, bicyclo [2.2.0]Hexyl, spiro [3.3]Heptyl and bicyclo [4.2.0]And (4) octyl.

The cycloalkyl group may be substituted. For example, it may be substituted by halogen, C_1～4Alkyl radical, C_1～4-haloalkyl group, C_1～4-alkoxy and/or cyano substitution.

Cycloalkylalkyl refers to cycloalkyl-alkyl groups, wherein the cycloalkyl and alkyl moieties are in accordance with the foregoing. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.

Alkyl ethers meaning C₃～C₁₂An alkoxyalkyl group. Suitable alkyl ether groups include methoxyethyl, ethoxyethyl, and methoxypropyl.

Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic group containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include those described above, which are substituted one or more times with: e.g. halogen, C_1～4Alkyl radical, C_1～4-haloalkyl, hydroxy, C_1～4-alkoxy, C_1～4Haloalkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxyl, cyano, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl and phenoxy.

Arylalkyl means aryl-alkyl in which the aryl and alkyl portions are in accordance with the foregoing. Preferably, the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety is straight or branched chain having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. The aryl moiety may be substituted with the substituents of the above aryl groups, while the alkyl moiety may be substituted with oxygen, halogen, cyano, or combinations thereof. Suitable examples include benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, fluorobenzyl, chlorobenzyl, methoxybenzyl, methylbenzyl and cyanobenzyl.

Heteroaryl refers to an aromatic heterocyclic ring having one or two rings and a total of 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom. Preferably the heteroaryl group contains 1 to 3, especially 1 or 2, heterocyclic atoms selected from N, O and S. Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, thioindenyl, isothiaindenyl, indolyl, isoindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl and benzoxazinyl, e.g. 2-thienyl, 3-thienyl, 2-, 3-or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl and 1-or 1-quinolyl, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl.

Substituted heteroaryl refers to the above heteroaryl substituted at one or more positions with: such as halogen, hydroxy, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.

Heteroarylalkyl refers to heteroaryl-alkyl wherein the heteroaryl and alkyl portions are in accordance with the foregoing. Suitable examples are pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl and isoquinolinylmethyl.

Heterocycle is a non-aromatic cyclic group containing at least one heterocyclic atom, preferably selected from N, S and O, such as 3-tetrahydrofuranyl, piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl.

Heterocycle-alkyl refers to heterocycle-alkyl wherein the heterocycle and alkyl moieties are in accordance with the foregoing. Suitable examples are piperidinyl-ethyl and pyrrolinyl-methyl.

The carbocycle is a monocyclic or bicyclic structure containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthalenyl and indan-2-yl.

Acyl refers to alkanoyl having 1 to 6 carbon atoms wherein the alkyl moiety may be substituted by halogen, alkyl, aryl and/or alkoxy, or aroyl having 7 to 15 carbon atoms wherein the aryl moiety may be substituted by, for example, halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl, acetyl, propionyl, butyryl and benzoyl.

The substituted group preferably has 1 to 3 substituents, particularly 1 to 2 substituents.

R¹Preferably H, alkyl groups such as methyl, ethyl and isopropyl, substituted alkyl groups such as HOCH₂CH₂Cycloalkyl groups such as cyclopropyl, cyclobutyl and cyclopentyl, cycloalkylalkyl groups such as cyclopropylmethyl. In particular, R¹Preferably methyl, ethyl or cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, especially methyl, ethyl and cyclopropyl.

R²Cycloalkyl, aryl, heteroaryl, carbocycle or heterocycle are preferred. In particular, R²Preferably cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl and norbornyl, aryl which is unsubstituted or substituted one or more times, for example by halogen, methoxy, nitro, cyano, amino or combinations thereof, heteroaryl which is unsubstituted or substituted, for example by methoxy and/or methylthio, such as pyridyl, pyrimidinyl, thienyl and furyl, carbocyclic such as substituted or unsubstituted 2-indanylOr heterocycles such as substituted or unsubstituted piperidinyl, pyrrolidinyl and tetrahydrofuranyl.

Furthermore, preferred PDE4 inhibitors according to the invention are compounds of the subformulae Ia to II, which correspond to formula I but have the following preferred groups:

Ia R¹is an unsubstituted or hydroxy-substituted alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 6 carbon atoms, or a cycloalkyl group having 3 to 5 carbon atoms; and

R²is an alkyl group having 3 to 8 carbon atoms, an alkyl ether having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 9 carbon atoms, a cycloalkylalkyl group having 4 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heterocyclic ring having 5 to 10 ring atoms, a hetero-alkyl group having 5 to 10 ring atoms, a carbocyclic ring having 5 to 12 carbon atoms, or a heteroaryl, heteroarylalkyl or arylalkyl group having 7 to 12 carbon atoms, wherein the heteroaryl or aryl moiety is unsubstituted or substituted one or more times by: halogen, alkyl, CN, alkoxy, nitro, alkoxy, or combinations thereof, and the alkyl moiety is unsubstituted or substituted with halogen.

Ib R¹Is cyclopropyl; and

R²is benzyl, phenethyl or phenylpropyl, which radicals are in each case substituted by halogen, C_1～4Alkyl radical, C_1～4-alkoxy or a combination thereof for 1 to 3 times.

Ic R¹Is cyclopropyl; and

R²is an alkyl group having 3 to 8 carbon atoms, or an arylalkyl group having 7 to 12 carbon atoms, wherein the aryl moiety is substituted one or more times with: halogen, alkyl, CN, alkoxy, nitro, or combinations thereof.

Id R¹Is cyclopropyl; and

R²is benzyl, 2-methylbenzyl, 3-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 3, 5-bis (trifluoromethyl) benzyl, 2, 4-difluorobenzyl, 3, 5-difluorobenzyl, 2, 6-difluorobenzyl, 2, 3-difluorobenzyl, 2-chloro-4-fluorobenzyl, 3-chloro-4-chlorobenzyl, 2-chloro-phenethyl, 2-fluoro-phenethyl, 2-methylphenylethyl, 3-chlorophenylethyl, 3-methylphenylethyl, 3-methoxyphenylethyl, 4-chlorophenylethyl, 4-methylphenylethyl, 4-methoxyphenylethyl, 2-methoxyphenylpropyl, 4-chlorophenylpropyl, 4-methoxyphenylpropyl.

Ie R¹Is cyclopropyl; and

R²is heteroarylalkyl which is unsubstituted or substituted by 1 to 3 halogen atoms, C_1～4Alkyl radical, C_1～4-alkoxy or a combination thereof.

If R¹Is cyclopropyl; and

R²is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl or 3-furylmethyl.

Ig R¹Is methyl, ethyl or cyclopropyl; and

R²is a cycloalkyl group.

Ih R¹Is methyl, ethyl or cyclopropyl; and

R²is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or norbornyl.

Ii R¹Is methyl, ethyl or cyclopropyl; and

R²is aryl (e.g., phenyl) or substituted aryl (e.g., substituted phenyl).

Ij R¹Is methyl, ethyl or cyclopropyl; and

R²is carbocyclic (e.g., 2-indanyl).

Ik R¹Is methyl, ethyl or cyclopropyl; and

R²is heterocyclic (e.g., piperidinyl).

Il R¹Is methyl, ethyl or cyclopropyl; and

R²is heteroaryl or substituted heteroaryl (e.g., substituted or unsubstituted pyrimidinyl, pyridinyl, thienyl, and furanyl).

Preferred aspects include pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, and optionally another active agent as described below; a method of inhibiting PDE4 enzymes, particularly isoenzymes, as determined in vitro or in vivo (in an animal, such as in an animal model, or in a mammal or in a human), e.g., by conventional assays or the assays described herein; methods of treating neurological syndromes, such as memory loss, particularly long-term memory loss, cognitive disorders or decline, memory disorders, and the like; a method of treating a disease mediated by PDE4 activity, such as a disease described herein, in a mammal, such as a human.

The compounds of the present invention can be prepared conventionally. Some of the methods that may be used are described below. All starting materials are known or can be prepared conventionally from known starting materials.

The 2-substituted hypoxanthine is prepared by standard methods in the art, such as by the neat reaction of 4-amino-5-imidazolecarboxamide with 2, 2, 2-trifluoroacetamide (E.Richter et al, J.Am.chem.Soc.1960, 82, 3144-. 6-halo-2-trifluoromethylpurines can be prepared by methods conventional in the art (see J. -J. Bourgugnon et al, J. Med. chem.1997, 40, 1768-1770; and H. Bader et al, U.S.National patent 4,405,781, 1983), for example by using halogenating agents such as SOCl₂Or POCl₃Or PCl₅The reaction is carried out. These reactions can be carried out by themselves or with polar aprotic solvents such as dichloromethane, dichloroethane or N, N-dimethylformamide. 6-halopurine (e.g., 6-chloro-2-trifluoromethylpurine) with alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or arylalkyl halides in a polar aprotic solvent such as N, N-dimethylformamide, dimethylsulfoxide, or dimethoxyethane in a base (e.g., K)₂CO₃、Na₂CO₃NaH) to give a mixture of 9-and 7-substituted 6-halopurines.

The use of a phase transfer catalyst, such as 18-crown-6 or tetrabutylammonium chloride, and elevated reaction temperatures, such as 60 ℃ to 150 ℃, can increase the reaction rate or reaction yield. Alternatively, 6-halopurine is reacted with an alkyl, cycloalkyl, arylalkyl, heteroaryl or cycloalkylalkyl alcohol under Mitsunobu conditions to provide a mixture of 9-and 7-substituted 6-halopurines. The 9-and 7-isomers prepared by the above reaction are easily separated by chromatography. The 9-substituted-6-halopurine is reacted with an amine (e.g., ammonia, an alkylamine, a cycloalkylamine, or a cycloalkylalkylamine) to provide adenine derivatives of formulas I-III.

Alternatively, 6-halo-2-substituted purines can be readily reacted with amines (e.g., ammonia, alkylamines, cycloalkylamines, or cycloalkylalkylamines) in the presence of polar protic solvents (e.g., methanol, ethanol, propanol, etc.) to provide 6-N-substituted adenine analogs. In a polar aprotic solvent such as N, N-dimethylformamide, dimethyl sulfoxide or dimethoxyethane in a base (e.g. K)₂CO₃、Na₂CO₃NaH) with an alkyl halide, cycloalkyl halide, cycloalkylalkyl halide, heteroaryl halide or arylalkyl halide to give adenine derivatives of the formulae I to IIIA compound (I) is provided. The use of a phase transfer catalyst, such as 18-crown-6 or tetrabutylammonium chloride, and elevated reaction temperatures, such as 60 ℃ to 150 ℃, can increase the reaction rate or reaction yield.

Alternatively, 6-N-substituted adenine is reacted with an alkyl alcohol, cycloalkyl alcohol, arylalkyl alcohol, heteroaryl alcohol or cycloalkylalkyl alcohol under Mitsunobu conditions to provide 9-substituted 6-N-substituted adenine of formulas I-III.

6-N-substituted-9-aryl-and 9-heteroaryl-adenosines can be synthesized by methods conventional in the art, for example, by reacting 4, 6-dichloro-5-aminopyrimidine with an appropriately substituted aniline or heteroarylamine to produce 4-arylamino or 4-heteroarylamino-6-chloropyrimidine, as described in J.L.Kelley et al, J.Med.Chem., 1997, 40, 3207. Cyclization is effected by treatment with triethyl orthoformate in the presence of an acid catalyst such as ethanesulfonic acid to give 6-chloro-9-aryl-or 9-heteroaryl-purines, which can be derivatized at the 6-N-position as described above to give adenine derivatives of formulae I-III.

Alternatively, 6-N-substituted adenine may be reacted with an arylboronic acid or heteroarylboronic acid in the presence of a base (e.g. triethylamine, pyridine, N-methylmorpholine), a copper catalyst (e.g. Cu (OAc)₂) And polar aprotic solvents (e.g., dichloromethane, 1, 4-dioxane, THF, DMF, CH)₃CN) in the presence of a coupling reaction in the manner described previously with respect to the modification of the N-arylation of imidazoles and pyrazoles (cf. P.Y.S.Lam et al Tetrahedron Lett.1998, 39, 2941-2944) to give 9-aryl-or 9-heteroaryl-adenine of the formulae I to III.

Thus, preference is given to using triethylamine as base instead of pyridine and in CH₃Heating to 50-60 ℃ in CN instead of in CH₂Cl₂Stirring at room temperature to provide the novel compound.

Alternatively, certain halogenated aryl and heteroaryl substrates can be subjected to aryl nucleophilic substitution reactions with 6- (substituted) amino-2-trifluoromethylpurines in polar aprotic solvents (e.g., DMF or DMSO) using bases (e.g., cesium carbonate) to give the target 9-aryl or 9-heteroarylpurines.

Many of these synthetic methods are described more fully in the examples below.

One skilled in the art will recognize that certain compounds of formulas I-III may exist in different geometric isomeric forms. In addition, certain compounds of the present invention have one or more asymmetric carbon atoms and thus can exist in the form of optical isomers and racemic or non-racemic mixtures thereof and diastereoisomers and diastereomeric mixtures thereof. All such compounds, including cis-isomers, trans-isomers, diastereomeric mixtures, racemates, diastereomeric mixtures of enantiomers, and substantially pure and pure enantiomers, are within the scope of the invention. Substantially pure enantiomers contain only no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.

Optical isomers can be obtained by resolution of racemic mixtures according to conventional methods, for example by formation of diastereomeric salts using optically active acids or bases, or formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. Different methods for separating optical isomers include the use of chiral chromatography (e.g., chiral HPLC columns) with or without conventional derivatization, and optimally selected to maximize separation of enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, which can be routinely selected. Also useful are derivatized or underivatized enzyme separations. The optically active compounds of the formulae I to III can likewise be obtained by chiral synthesis using optically active starting materials.

The invention also relates to useful forms of the compounds disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all compounds of the invention. Pharmaceutically acceptable salts include salts obtained by reacting the main compound used as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, and citric acid. Pharmaceutically acceptable salts also include salts such as: wherein the main compound acts as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. Those skilled in the art will also recognize that acid addition salts of the claimed compounds may be prepared by reacting the compounds with suitable inorganic or organic acids via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the present invention with a suitable base via a variety of known methods.

The following are further examples of acid salts that may be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, methanesulfonate, and undecanoate.

Preferably, the salt formed is pharmaceutically acceptable for administration to a mammal. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example for isolating the compound in salt form and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base may then be converted into a pharmaceutically acceptable acid addition salt, if desired.

The compounds of the invention may be administered alone or as the active ingredient of the formulation. Accordingly, the invention also includes pharmaceutical compositions of compounds of formula I, containing, for example, one or more pharmaceutically acceptable carriers.

There are a number of standard references which describe the preparation of various formulations suitable for administration of the compounds of the present invention. Examples of possible formulations and preparations are included in the following documents, for example: the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); pharmaceutical Dosage Forms: tablets (Lieberman, Lachman and Schwartz, editors) current edition, Marcel Dekker, Inc. published, and Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-.

Due to the high degree of PDE4 inhibition of the compounds of the invention, they can be administered to anyone in need or desire of PDE4 inhibition and/or improved cognition. Administration can be carried out as needed by the patient, for example, oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal, and infusion), inhalation, rectal, vaginal, topical, localized, transdermal, and ocular.

Various solid oral dosage forms may be used for administration of the compounds of the present invention, including the following solid dosage forms: tablets, gelcaps (gelcaps), capsules, caplets, granules, lozenges, and powders. The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannose, lactose, starch) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in the administration of the compounds of the present invention.

Various liquid oral dosage forms may also be used for administration of the compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. These dosage forms may also contain suitable inert diluents known in the art, such as water, and suitable excipients known in the art, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and/or suspending the compounds of the present invention. For example, the compounds of the present invention may be injected intravenously in the form of an isotonic sterile solution. Other formulations are also possible.

Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be in the form of a pessary, tampon, cream, gel, paste, foam or spray containing the active ingredient and a suitable carrier as known in the art.

For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, liniment, lotion, emulsion, suspension, gel, solution, paste, powder, spray, and drops suitable for administration to the skin, eye, ear, or nose. Topical administration may also include transdermal administration via a device such as a transdermal patch.

Aerosol formulations suitable for administration by inhalation may also be prepared. For example, for the treatment of respiratory diseases, the compounds of the present invention may be administered by inhalation of powders (e.g. micronised) or as nebulized solutions or suspensions. The aerosol formulation may be placed in a propellant that can be pressurized.

The compounds may also be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents useful in the treatment of cognitive disorders and/or the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, cholinergics, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigmine (rivastigmine), and glanthamine). In these combinations, each active ingredient may be administered in accordance with their conventional dosage ranges or dosages below their conventional dosage ranges.

The invention also includes therapeutic methods involving inhibition of the PDE4 enzyme. Accordingly, the invention includes a method of selectively inhibiting the PDE4 enzyme in an animal, such as a mammal, particularly a human, wherein such inhibition has a therapeutic effect, e.g., such inhibition may ameliorate a condition involving neurological syndrome, such as memory, particularly long-term memory loss. These methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof, an inhibitory amount of a compound disclosed herein, alone or as part of a formulation.

Symptoms of memory impairment manifest as a dysfunction in the ability to learn new information and/or an inability to recall previously learned information. Memory disorders are the major symptoms of dementia and may also be syndromes associated with diseases such as alzheimer's disease, schizophrenia, parkinson's disease, huntington's disease, pick's disease, creutzfeldt-jakob disease, HIV, cardiovascular disease and head trauma, as well as age-related cognitive decline.

Dementia is a disease involving memory loss and other intellectual impairment independent of memory. The invention includes methods for treating patients with memory impairment of all forms of dementia. Dementias are classified according to their etiology and include: neurodegenerative dementias (such as alzheimer's disease, parkinson's disease, huntington's disease, pick's disease), vascular (such as infarction, hemorrhage, heart disease), mixed vascular and alzheimer's disease, bacterial meningitis, creutzfeldt-jakob disease, multiple sclerosis, traumatic (such as subdural hematoma or traumatic brain injury), infectious (such as HIV), hereditary (down's syndrome), toxic (such as heavy metals, alcohol, certain drugs), metabolic (such as vitamin B12 or folate deficiency), CNS hypoxia, cushing's syndrome, psychiatric disorders (such as depression and schizophrenia), and hydrocephalus.

The invention includes methods for treating memory loss independent of dementia, including Mild Cognitive Impairment (MCI) and age-related cognitive decline. The invention includes methods for treating memory impairment resulting from disease. In another application, the invention includes methods for treating memory loss due to the use of general anesthetics, chemotherapy, radiation therapy, post-operative trauma, and therapeutic intervention.

The compounds of the invention may be used for the treatment of psychiatric disorders including schizophrenia, bipolar or manic depression, major depression, and drug addiction and morphine dependence. These compounds can improve insomnia. PDE4 inhibitors can be used to elevate cAMP levels and prevent neuronal apoptosis. PDE4 inhibitors are also known to be anti-inflammatory agents. The combination of anti-apoptotic and anti-inflammatory properties makes these compounds useful for treating neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, neurogenesis, alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), and Multiple System Atrophy (MSA).

Thus, according to a preferred embodiment, the invention comprises a method for treating patients suffering from memory impairment due to diseases such as: alzheimer's disease, schizophrenia, parkinson's disease, huntington's disease, pick's disease, creutzfeldt-jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, brain aging, multi-infarct dementia and other neurological disorders, including acute neuropathy, and HIV and cardiovascular disease, comprising administering an effective amount of a compound of formula (I) or (Γ) or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may also be used in a method of treating a patient suffering from a disease characterized by reduced NMDA function, such as schizophrenia. The compounds may also be used to treat psychiatric disorders characterized by elevated levels of PDE4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychosis and neuropathy.

As noted, the compounds of the present invention also exhibit anti-inflammatory activity. Accordingly, the compounds of the present invention are useful in the treatment of various allergic and inflammatory diseases, particularly disorders characterized by reduced levels of cyclic AMP and/or increased levels of phosphodiesterase 4. Thus, according to another embodiment of the present invention, there is provided a method of treating allergic and inflammatory conditions, said method comprising administering an effective amount of a compound of formula (I) or (Γ), or a pharmaceutically acceptable salt thereof. These conditions include: asthma, chronic bronchitis, Chronic Obstructive Pulmonary Disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis of the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, chronic inflammatory bowel disease, follicular and large-area pyoderma, endogenous and exogenous acne, rosacea, Behcet's disease, allergic purpuric nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastroenteropathy, autoimmune disease, etc.

PDE4 inhibitors for the treatment of asthma, chronic bronchitis, psoriasis, allergic rhinitis and other inflammatory diseases and for the inhibition of tumor necrosis factor are known in the art. See, for example, WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651 and US 5,935,9778. These references also describe assays for determining PDE4 inhibitory activity, as well as methods for synthesizing these compounds. These documents are incorporated herein by reference in their entirety.

PDE4 inhibitors may be used for the prevention or amelioration of osteoporosis, as antibiotics, for the treatment of cardiovascular disease by mobilizing cholesterol in atherosclerotic lesions, for the treatment of Rheumatoid Arthritis (RA), for the long-term inhibition of mesenchymal cell proliferation after transplantation, for the treatment of urethral obstruction secondary to benign prostatic hyperplasia, for the inhibition of chemotaxis and reduction of colon cancer cell invasion, for the treatment of B-cell chronic lymphocytic leukemia (B CLL), for the inhibition of uterine contractility, for the reduction of pulmonary vascular Ischemia Reperfusion Injury (IRI), for corneal hydration, for the inhibition of IL-2R expression, thereby eliminating HIV-1DNA nuclei from entering memory T cells, for the increase of glucose-induced insulin secretion, for the simultaneous prevention and treatment of colitis, and for the inhibition of mast cell degranulation.

The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents useful in the treatment of cognitive disorders and/or the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, cholinergics, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigmine, and glanthanamine). In these combinations, each active ingredient may be administered in accordance with their conventional dosage ranges or dosages below their conventional dosage ranges.

The dosage of the compounds of the invention depends on a variety of factors including the particular syndrome being treated, the severity of the symptoms, the route of administration, the frequency of the dosage intervals, the particular compound used, the potency, toxicological profile, pharmacokinetic profile of the compound and the presence of any deleterious side effects, etc.

The compounds of the invention are typically administered to a mammal at conventional dosage levels for PDE4 inhibitors, such as the known compounds described above. For example, the compounds may be administered in one or more doses, for example at an oral dose level of 0.01 to 100 mg/kg/day, preferably 0.1 to 70 mg/kg/day, especially 0.5 to 10 mg/kg/day. For example, a unit dosage form may contain 0.1 to 50mg of active compound. For intravenous administration, the compounds may be administered in one or more doses, and the dose level is, for example, 0.001 to 50 mg/kg/day, preferably 0.001 to 10 mg/kg/day, particularly 0.01 to 1 mg/kg/day. For example, a unit dosage form may contain 0.1 to 10mg of active compound.

In practicing the methods of the present invention, it will of course be understood that reference to particular buffers, media, reagents, cells, culture conditions, and the like, is not intended to be limiting, but is intended to include all such related materials which one of ordinary skill in the art would recognize as being useful or valuable in the particular context in question. For example, one buffer system or medium can often be substituted for another while still achieving similar, if not identical, effects. Those skilled in the art are well aware of such systems and methods and are therefore able to make such substitutions without undue experimentation to best serve their purposes in using the methods and steps disclosed herein.

The invention will now be further described by the following non-limiting examples. In practicing the disclosure of these examples, it should be clearly understood that they are no doubt indicative of those skilled in the art as to other and different embodiments of the disclosed method.

In the foregoing and following examples, all temperatures are given in degrees Celsius without calibration; and all parts and percentages are by weight unless otherwise indicated.

All applications, patents, and publications cited above and below are incorporated herein by reference in their entirety.

Example 1

1, 9-dihydro-2-trifluoromethyl-6H-purin-6-one (Kelly, J.L.; Linn, J.A.; Selway, J.W.T., J.Med.Chem., 1989, 32, 1757-

A1L round bottom flask (three necks) containing 340g of trifluoroacetamide was heated in an oil bath at 110 deg.C. After the trifluoroacetamide was melted, 50g of 5-aminoimidazole-4-carboxamide-HCl was added. The mixture was heated to reflux (bath temperature 160-165 ℃) for 4 hours, cooled to room temperature, and the firm solid was triturated with 1L of diethyl ether. The ether was decanted and the residual solid was melted by heating and 200mL of ether was added from the dropping funnel through a water-cooled condenser. The mixture was cooled to room temperature and an additional 200mL of diethyl ether was added with stirring. The solid was removed by filtration, triturated with 3X 500mL diethyl ether, and triturated with 200mL H₂O wash and filter to give 89g of crude product. The product was treated with 3L MeOH and 9g activated carbon, heated to reflux for 20 min, filtered through a celite pad, and concentrated to a volume of 2.5L. This material was heated to dissolve all the precipitate formed and then slowly cooled to room temperature. The crystalline material was isolated by filtration and dried under vacuum to give 41g of the target hypoxanthine as a white solid.¹H NMR(DMSO-d₆)δ8.34(s，1H)，7.18(bs，2H)。MS(ES+)，205.0(100％，M+H)。

Example 2

6-chloro-2-trifluoromethylpurine

15g (73mmol) of 2-trifluoromethylhypoxanthine and 300mL of CHCl₃The mixture of (2) was heated to reflux and 26.7mL (366mmol) of SOCl was used₂And 28.3mL (366mmol) of DMF. The reaction was held at reflux for 1.5 hours, cooled to room temperature, and poured into 1.2L of ice water. The organic layer was separated and used 2X 300mL H₂And O washing. With saturated NaHCO₃The pH of the combined aqueous phases was adjusted to 7 and extracted with 3X 1.2L of diethyl ether. The combined ether and chloroform extracts were dried (MgSO)₄) And concentrated to dryness to give 7.4g of crude product.¹H NMR(DMSO-d₆)δ14.45(bs，1H)，8.95(s，1H)。MS(ES+)222.96(100％，M+H)。

Example 3

6-chloro-9- (2-fluorobenzyl) -2-trifluoromethylpurine

5g (22.5mmol) of 6-chloro-2-trifluoromethylpurine,4.05g (29.4mmol) of anhydrous K₂CO₃A mixture of 56mL anhydrous DMF and 3.55mL (29.4mmol) 2-fluorobenzyl bromide was stirred for 16 h. The reaction mixture was poured into 50mL of ice water, and the pH of the solution was adjusted to 5 or 6 with acetic acid. The mixture was extracted with 3X 300mL of diethyl ether and 3X 350mL of H₂The combined organic portions were washed with O, 300mL brine and dried (Na)₂SO₄) And concentrated in vacuo to give a yellow oil. Chromatographic purification on silica gel with a gradient elution of 20% EtOAc in hexane to 50% EtOAc in hexane afforded 3.5g (47% yield) of the target 9-isomer (first eluate) and 1.97g (27% yield) of the 7-isomer.¹H NMR(CDCl₃)δ8.33(s，1H)，7.50-7.47(m，1H)，7.40-7.38(m，1H)，7.20-7.11(m，2H)，5.56(s，2H)。

Example 4

6-cyclopropylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

A mixture of 100mg (0.30mmol) 6-chloro-9- (2-fluorobenzyl) -2-trifluoromethylpurine, 1mL (14mmol) aminocyclopropane and 5mL EtOH was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH₂Cl₂Using 2X 5mL of H₂O, 5mL brine wash, dry (Na)₂SO₄) And concentrated. Chromatography on silica gel using 33% EtOAc in hexane as eluent gave 102mg (97% yield) of the title product. M.P.118.5-119.0 ℃;¹H NMR(CDCl₃)δ7.892(s，1H)，7.50-7.39(m，1H)，7.37-7.29(m，1H)，7.18-7.05(m，2H)，5.95(bs，1H)，5.44(s，2H)，0.94-0.91(m，2H)，0.65-0.64(m，2H)。

to obtain the methanesulfonate (methansulfonate salt or mesylate salt), 4ml of 0.1N CH in EtOAc are added₃SO₃H was added to a solution of 145mg (0.4mmol) 6-cyclopropylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine in EtOAc. 1ml of hexane was then added to the warm solution and the resulting mixture was allowed to crystallize (in the refrigerator). The solid was collected to give 148mg of the mesylate salt. The salt is in H₂O is relatively insoluble. MP.167.5 to 169.0 ℃; m.p.114-118 ℃ for the free base.

The following compounds were prepared in a similar manner to that described above:

a.6-methylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

6-ethylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

c.6-amino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

6-N-Cyclopropylmethylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

e.6- [1- (2-hydroxy) ethyl ] amino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

f.6-Cyclopentylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

g.6-Cyclohexylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

h.6-isopropylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

Example 5

6-Cyclopropylamino-2-trifluoromethylpurine

A mixture of 12g (54mmol) of 6-chloro-2-trifluoromethylpurine, 30g (540mmol) of cyclopropylamine and 250mL of ethanol was stirred at room temperature for 4.5 days, leaving a white solid. The mixture was concentrated to dryness in vacuo and 215mL of H were added₂O, and the mixture was stirred for 1 hour. The product was collected by filtration and after drying (vacuum oven, 50 ℃, 5 hours) 8.1g of product was obtained in 62% yield. M.P.260 ℃;¹H NMR(CD₃OD)δ8.18(s，1H)，3.30(bs，1H)，0.904(m，2H)，0.67(m，2H)。

the following compounds were prepared in a similar manner:

a.6-methylamino-2-trifluoromethylpurine

6-Cyclopentylamino-2-trifluoromethylpurine

Example 6

6-cyclopropylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

To a nitrogen-flushed tube with a stir bar were added 25mg (0.13mmol) 2-fluorobenzyl bromide, 0.7mL anhydrous DMF, 18mg (0.13mmol) K₂CO₃And 0.5mL (0.10mmol) of 0.2M 6-cyclopropylamino-2-trifluoromethyladenine in anhydrous DMF. The reaction was stirred at room temperature for 18 hours, quenched with 2mL of ice water, and adjusted to pH 5-6 with acetic acid. The aqueous mixture was extracted with 10mL of diethyl ether and 3mL of H₂O, 3mL brine washed ether portion, dried (MgSO)₄) And concentrated to dryness under vacuum. M.P.118.5-119.0 ℃;¹H NMR(CDCl₃)δ7.892(s，1H)，7.50-7.39(m，1H)，7.37-7.29(m，1H)，7.18-7.05(m，2H)，5.95(bs，1H)，5.44(s，2H)，0.94-0.91(m，2H)，0.65-0.64(m，2H)。

the following compounds were prepared in a similar manner:

a.6-cyclopropylamino-9- (3-methoxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-chlorobenzyl) -2-trifluoromethylpurine

c.6-cyclopropylamino-9- (3-nitrobenzyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (4-cyanobenzyl) -2-trifluoromethylpurine

e.6-cyclopropylamino-9- (4-trifluoromethylbenzyl) -2-trifluoromethylpurine

f.6-cyclopropylamino-9- (3, 4-dichlorobenzyl) -2-trifluoromethylpurine

g.6-cyclopropylamino-9- (4-chlorobenzyl) -2-trifluoromethylpurine

h.6-cyclopropylamino-9- (3, 4-difluorobenzyl) -2-trifluoromethylpurine

i.6-cyclopropylamino-9- (3-pyridylmethyl) -2-trifluoromethylpurine

j.6-cyclopropylamino-9- [ alpha- (2-chloroacetophenone) ] -2-trifluoromethylpurine

k.6-cyclopropylamino-9- [ alpha- (4-methoxyacetophenone) ] -2-trifluoromethylpurine

6-Cyclopropylamino-9- (3, 5-difluorobenzyl) -2-trifluoromethylpurine

m.6-cyclopropylamino-9-ethyl-2-trifluoromethylpurine

n.6-cyclopropylamino-9- [ alpha- (4-methylacetophenone) ] -2-trifluoromethylpurine

o.6-cyclopropylamino-9- (3-trifluoromethylbenzyl) -2-trifluoromethylpurine

p.6-cyclopropylamino-9- (3, 5-bistrifluoromethylbenzyl) ] -2-trifluoromethylpurine

q.6-cyclopropylamino-9- (4-methylsulfonylbenzyl) ] -2-trifluoromethylpurine

r.6-Cyclopropylamino-9- (4-nitrobenzyl) -2-trifluoromethylpurine

s.6-cyclopropylamino-9- (4-tert-butylbenzyl) -2-trifluoromethylpurine

t.6-cyclopropylamino-9- (1-pentan-3-one) -2-trifluoromethylpurine

u.6-cyclopropylamino-9- [ alpha- (2-methoxyacetophenone) ] -2-trifluoromethylpurine

v.6-cyclopropylamino-9- [ alpha- (4-cyanoacetophenone) ] -2-trifluoromethylpurine

w.6-cyclopropylamino-9- [ alpha- (3-chloroacetophenone) ] -2-trifluoromethylpurine

x.6-cyclopropylamino-9- [ alpha- (3-methoxyacetophenone) ] -2-trifluoromethylpurine

y.6-cyclopropylamino-9- [ alpha- (4-chloroacetophenone) ] -2-trifluoromethylpurine

z.6-cyclopropylamino-9- [ alpha- (3, 4-dichloroacetophenone) -2-trifluoromethylpurine

aa.6-cyclopropylamino-9- (4-pyridylmethyl) -2-trifluoromethylpurine

bb.6-cyclopropylamino-9- (2-pyridylmethyl) -2-trifluoromethylpurine

cc., 6-cyclopropylamino-9- (4-ethylbenzyl) -2-trifluoromethylpurine

dd.6-cyclopropylamino-9- (3, 4-dimethoxybenzyl) -2-trifluoromethylpurine

ee.6-cyclopropylamino-9- (2, 4-dichlorobenzyl) -2-trifluoromethylpurine

ff.6-cyclopropylamino-9- (2, 3-dichlorobenzyl) -2-trifluoromethylpurine

gg.6-cyclopropylamino-9- (3, 4-ethylenedioxybenzyl) -2-trifluoromethylpurine

hh.6-cyclopropylamino-9- (3, 4-methylenedioxybenzyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (4-isopropylbenzyl) -2-trifluoromethylpurine

jj.6-Cyclopropylamino-9- (3-thienylmethyl) -2-trifluoromethylpurine

kk.6-cyclopropylamino-9- (2-thienylmethyl) -2-trifluoromethylpurine

ll.6-cyclopropylamino-9- (2-furylmethyl) -2-trifluoromethylpurine

mm.6-cyclopropylamino-9- (3-furylmethyl) -2-trifluoromethylpurine

nn.6-Cyclopropylamino-9- [1- (2- (2-chlorophenyl) ethyl) ] -2-trifluoromethylpurine

oo.6-Cyclopropylamino-9- [1- (2- (2-fluorophenyl) ethyl) ] -2-trifluoromethylpurine

6-Cyclopropylamino-9- [1- (2- (2-toluoyl) ethyl) ] -2-trifluoromethylpurine

qq.6-Cyclopropylamino-9- [1- (2- (3-chlorophenyl) ethyl) ] -2-trifluoromethylpurine

rr.6-Cyclopropylamino-9- [1- (2- (3-toluoyl) ethyl) ] -2-trifluoromethylpurine

ss.6-cyclopropylamino-9- [1- (2- (3-methoxyphenyl) ethyl) ] -2-trifluoromethylpurine

tt.6-Cyclopropylamino-9- [1- (2- (4-chlorophenyl) ethyl) ] -2-trifluoromethylpurine

uu.6-cyclopropylamino-9- [1- (2- (4-toluoyl) ethyl) ] -2-trifluoromethylpurine

vv.6-cyclopropylamino-9- [1- (2- (4-methoxyphenyl) ethyl) ] -2-trifluoromethylpurine

ww.6-Cyclopropylamino-9- [1- (3- (2-methoxyphenyl) propyl) ] -2-trifluoromethylpurine

xx.6-cyclopropylamino-9- [1- (3- (4-chlorophenyl) propyl) ] -2-trifluoromethylpurine

yy.6-cyclopropylamino-9- [1- (3- (4-methoxyphenyl) propyl) ] -2-trifluoromethylpurine

zz.6-cyclopropylamino-9- (3-benzyloxybenzyl) -2-trifluoromethylpurine

aaa.6-cyclopropylamino-9- (2, 6-difluorobenzyl) -2-trifluoromethylpurine

bbb.6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine

ccc.6-cyclopropylamino-9- (1-propyl) -2-trifluoromethylpurine

ddd.6-cyclopropylamino-9- (2, 3-difluorobenzyl) -2-trifluoromethylpurine

eee.6-cyclopropylamino-9- (4-fluorobenzyl) -2-trifluoromethylpurine

fff.6-cyclopropylamino-9- (2-chlorobenzyl) -2-trifluoromethylpurine

ggg.6-cyclopropylamino-9- (3-methylbenzyl) -2-trifluoromethylpurine

hhh 6-cyclopropylamino-9- (2-chloro-4-fluorobenzyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- [1- (2-methoxyethyl) ] -2-trifluoromethylpurine

jjjj.6-Cyclopropylamino-9- (2-butyl) -2-trifluoromethylpurine

kkk.6-cyclopropylamino-9- (1-butyl) -2-trifluoromethylpurine

lll.6-Cyclopropylamino-9- (2-methylbenzyl) -2-trifluoromethylpurine

mmm.6-cyclopropylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

nnn.6-cyclopropylamino-9- (2, 4-difluorobenzyl) -2-trifluoromethylpurine

ooo.6-cyclopropylamino-9- (2-nitrobenzyl) -2-trifluoromethylpurine

ppp.6-cyclopropylamino-9-benzyl-2-trifluoromethylpurine

qqq.6-Cyclopropylamino-9- (2-propyl) -2-trifluoromethylpurine

rrr.6-Cyclopropylamino-9- (2-trifluoromethylbenzyl) -2-trifluoromethylpurine

sss.6-cyclopropylamino-9- (3-fluorobenzyl) -2-trifluoromethylpurine

ttt.6-Cyclopropylamino-9- (4-phenylbenzyl) -2-trifluoromethylpurine

uuu.6-cyclopropylamino-9- (2-phenylbenzyl) -2-trifluoromethylpurine

vvv.6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine

www.6-cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine

The following compounds can be prepared in a similar manner as described in example 6 using cesium carbonate instead of potassium carbonate:

a.6-cyclopropylamino-9- (2, 6-dichloro-4-pyridylmethyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (4-methoxybenzyl) -2-trifluoromethylpurine

c.6-cyclopropylamino-9- (3-nitrobenzyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (2-pyrimidinyl) -2-trifluoromethylpurine

e.6-cyclopropylamino-9- (4- (2-diethylamino) pyrimidinyl) -2-trifluoromethylpurine

f.6-cyclopropylamino-9- (4- (2-chloro) pyrimidinyl) -2-trifluoromethylpurine

g.6-cyclopropylamino-9- (4- (2-methylsulfanyl) pyrimidinyl) -2-trifluoromethylpurine.

In a similar manner to that described above, using 6-N-methylamino-2-trifluoromethylpurine as starting material, the following compounds were prepared:

a.6-N-methylamino-9-cyclopentyl-2-trifluoromethylpurine

6-N-methylamino-9-cycloheptyl-2-trifluoromethylpurine

In a similar manner to that described above, using 6-N-cyclopentylamino-2-trifluoromethylpurine as starting material, the following compounds were prepared:

6-N-Cyclopentylamino-9-methyl-2-trifluoromethylpurine.

Example 7

6-cyclopropylamino-9- (3-aminophenyl) -2-trifluoromethylpurine

A mixture of 6-cyclopropylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine (0.1mmol), palladium on activated carbon (0.001mol), methanol (50ml) and acetic acid (3ml) was shaken under a hydrogen atmosphere of 30 psi. After 5 hours, the reaction mixture was filtered over celite and the filtrate was concentrated in vacuo. Removing the residueThe retentate is dissolved in 30mL of ethyl acetate, washed with 30mL of 5% aqueous sodium bicarbonate solution, concentrated and washed with SiO₂Purification by chromatography gave the amino product in quantitative yield.

¹H NMR(300MHz，CDCl₃)δ8.10(s，1H)，7.27(t，J＝8.1Hz，1H)，7.05(s，1H)，6.98(d，J＝8.1Hz，1H)，6.70(d，J＝8.1Hz，1H)，6.35(b，1H)，3.18(b，1H)，0.91(m，2H)，0.69(m，2H)。

The following compounds were prepared in a similar manner:

6-cyclopropylamino-9- (3-aminobenzyl) -2-trifluoromethylpurine

Example 8

6-cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine (Pragnacharryu, P.V.P.; Varkhedkar, V.; Curtis, M.A.; Chang, I.F.; Abushanab, E.J.Med.chem., 2000, 43, 4694-

To 20mg (0.08mmol) of 6-cyclopropylamino-2-trifluoromethylpurine, 42mg (0.16mmol) of PPh in THF under an atmosphere of N2 with magnetic stirring₃And 18mg (0.21mmol) cyclopentanol 48mg (0.23mmol) DIAD was added. The resulting mixture was stirred at room temperature for 16 hours, concentrated, and placed in 10mL of H₂O, and extracted with 2X 15mL of diethyl ether. The organic layers were combined and washed with water (MgSO)₄) Dried, concentrated in vacuo and applied to CH₂Cl₂Purification by silica gel chromatography with 10% MeOH in silica gel afforded the desired product.¹H NMR(CDCl₃)7.92(s，1H)，6.01(bs，1H)，4.98(p，1H)，3.18(bs，1H)，2.36-2.25(m，2H)，2.03-1.79(m，6H)，0.86(dd，2H)，0.65(dd，2H)。

The following compounds were prepared in a similar manner:

a.6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine

6-Cyclopropylamino-9-cyclopentylethyl-2-trifluoromethylpurine

c.6-Cyclopropylamino-9-cyclopentylpropyl-2-trifluoromethylpurine

6-Cyclopropylamino-9- (3- (1-ethyl-pyrrolidinyl) -2-trifluoromethylpurine

e.6-cyclopropylamino-9- (3- (1-ethyl-piperidinyl) -2-trifluoromethylpurine

f.6-cyclopropylamino-9- (2- (1-ethyl-piperidinyl) -2-trifluoromethylpurine

g.6-cyclopropylamino-9- (piperidin-1-ylethyl) -2-trifluoromethylpurine

h.6-cyclopropylamino-9- (2- (1-methyl-piperidinyl) -2-trifluoromethylpurine

i.6-cyclopropylamino-9- (5-oxo- (S) -pyrrolidin-3-yl) -2-trifluoromethylpurine

j.6-cyclopropylamino-9- (5-oxo- (R) -pyrrolidin-3-yl) -2-trifluoromethylpurine

Example 9

6-cyclopropylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine

A mixture of 6-cyclopropylamino-2-trifluoromethyladenine (46mg, 0.2mmol), 3, 4-dimethoxyphenylboronic acid (44mg, 0.24mmol), copper (II) acetate (36mg, 0.2mmol), triethylamine (1.0mmol, 101mg), anhydrous acetonitrile (4ml) and molecular sieves (. about.10 beads) was stirred at 50-55 ℃ for 18 hours. Ethyl acetate (20ml) was added and the solid was filtered off. The filtrate was washed with 20ml of 5% aqueous sodium bicarbonate solution. Evaporated and eluted at SiO using hexane/ethyl acetate/methanol (50: 1)₂Chromatography was performed thereon to obtain 7.9mg of the title compound (yield 10%).¹H NMR(300MHz，CDCl₃)δ8.10(s，1H)，7.39(s，1H)，7.13(d，J＝8.7Hz，2H)，6.98(d，J＝8.7Hz，2H)，6.35(b，1H)，3.93(s，3H)，3.90(s，3H)，3.18(b，1H)，0.91(m，2H)，0.69(m，2H)。

The following compounds were prepared in a similar manner:

a.6-cyclopropylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (3-methoxyphenyl) -2-trifluoromethylpurine

c.6-cyclopropylamino-9- (4-methoxyphenyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine

e.6-cyclopropylamino-9- (2-methoxyphenyl) -2-trifluoromethylpurine

f.6-cyclopropylamino-9- (3-cyanophenyl) -2-trifluoromethylpurine

g.6-cyclopropylamino-9- (2, 5-dimethoxyphenyl) -2-trifluoromethylpurine

h.6-cyclopropylamino-9- (2, 4-dimethoxypyrimidinyl) -2-trifluoromethylpurine

i.6-cyclopropylamino-9- (2-methoxy-5-pyridyl) -2-trifluoromethylpurine

j.6-cyclopropylamino-9- (4-pyridyl) -2-trifluoromethylpurine

k.6-cyclopropylamino-9- (3-pyridyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (1-tert-butoxycarbonyl-pyrrol-2-yl) -2-trifluoromethylpurine

m.6-cyclopropylamino-9- (4-dimethylaminophenyl) -2-trifluoromethylpurine

n.6-methylamino-9- (2, 4-dimethoxy-5-pyrimidinyl) -2-trifluoromethylpurine

o.6-methylamino-9- (2-methoxyphenyl) -2-trifluoromethylpurine

p.6-methylamino-9- (4-methoxyphenyl) -2-trifluoromethylpurine

q.6-methylamino-9- (3-acetylphenyl) -2-trifluoromethylpurine

r.6-methylamino-9- (3-methoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine

t.6-cyclopropylamino-9- (3-furyl) -2-trifluoromethylpurine

u.6-cyclopropylamino-9- (4-ethoxyphenyl) -2-trifluoromethylpurine

v.6-cyclopropylamino-9- (2-ethoxyphenyl) -2-trifluoromethylpurine

w.6-cyclopropylamino-9- (3, 4-methylenedioxyphenyl) -2-trifluoromethylpurine

x.6-cyclopropylamino-9- (3-ethoxyphenyl) -2-trifluoromethylpurine

y.6-methylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine

z.6-cyclopropylamino-9- (3, 5-dimethoxyphenyl) -2-trifluoromethylpurine

aa.6-cyclopropylamino-9- (2-methoxy-5-chlorophenyl) -2-trifluoromethylpurine

bb.6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine

cc.6-Cyclopropylamino-9- (2-fluorophenyl) -2-trifluoromethylpurine

dd.6-cyclopropylamino-9- (4-fluorophenyl) -2-trifluoromethylpurine

ee.6-cyclopropylamino-9- (4-chlorophenyl) -2-trifluoromethylpurine

ff.6-cyclopropylamino-9- (4-toluoyl) -2-trifluoromethylpurine

gg.6-cyclopropylamino-9- (4-trifluoromethylphenyl) -2-trifluoromethylpurine

hh.6-Cyclopropylamino-9- (3-thienyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (3-trifluoromethylphenyl) -2-trifluoromethylpurine

Example 10

In vitro assay for phosphodiesterase type 4 inhibitory activity

Human PDE4 was obtained from baculovirus-infected Sf9 cells expressing the recombinase. The cDNA encoding hPDE-4D6 was subcloned into a baculovirus vector. Insect cells (Sf9) were infected with this baculovirus and cells were cultured until the protein was expressed. Baculovirus-infected cells were lysed and the lysate was used as a source of hPDE-4D6 enzyme. The enzyme was partially purified by DEAE ion exchange chromatography. This process can be repeated using cDNAs encoding other PDE-4 enzymes.

The determination method comprises the following steps:

phosphodiesterase type 4 converts cyclic adenosine monophosphate (cAMP) to 5 '-adenosine monophosphate (5' -AMP). Nucleotidase converts 5' -AMP to adenosine. Thus, the combined activity of PDE4 and nucleotidase converts cAMP to adenosine. cAMP and adenosine were easily separated by a neutral alumina column. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay, and thus PDE4 inhibitors result in a decrease in adenosine.

The cell lysate expressing hPDE-4D6 (40. mu.l) was combined with 50. mu.l of assay mix and 10. mu.l of inhibitor and incubated for 12 minutes at room temperature. The final concentrations of the analytical components were: 0.4. mu.g of enzyme, 10mM Tris-HCl (pH 7.5), 10mM MgCl₂3 μ M cAMP, 0.002U 5' -nucleotidase, and 3X 10⁴cpm[3H]cAMP. The reaction was stopped by adding 100. mu.l of boiled 5 mNHCl. An aliquot of 75. mu.l of the reaction mixture was transferred from each well onto an alumina column (Multiplate; Millipore). Elution of labelled adenosine into OptiPlate by spinning at 2000rpm for 2 minutes; add 150. mu.l/well of scintillation fluid to the OptiPlate. The plate was closed, shaken for about 30 minutes, and Wallac was used

Measurement [2 ]³H]Cpm of adenosine.

All test compounds were dissolved in 100% DMSO and diluted to assay, resulting in a final DMSO concentration of 0.1%. DMSO at this concentration did not affect enzyme activity.

A decrease in adenosine concentration represents an inhibition of PDE activity. pIC was determined by screening 6-12 compound concentrations ranging from 0.1nM to 10000nM₅₀Values, then plotting drug concentration pairs³Graph of H-adenosine concentration. Using non-Linear regression software (Assay)) Estimating pIC₅₀The value is obtained.

Example 11

Passive avoidance in rats, in vivo testing for learning and memory

The experiments were performed as described previously (Zhang, h. -t., Crissman, a.m., Dorairaj, n.r., Chandler, l.j. and O' Donnell, j.m., Neuropsychopharmacology, 2000, 23, 198-. The instrument (Model E10-16SC, Coulbourn Instruments, Allentown, Pa.) consisted of a double compartment, where the illuminated compartment was connected to the darkened compartment by a shutter. The dark compartment door consists of a stainless steel rod through which a foot shock from a constant current source is provided. All experimental groups were first fitted to the instrument the day before the start of the experiment. During training, rats (male Spraque-Dawley (Harlan), weighing 250-350 g) were placed in the illuminated compartment facing the closed gate 1 minute before lifting the gate. The waiting time to enter the dark compartment was recorded. After the rat entered the dark compartment, the door was closed and a 0.5mA shock was applied for 3 seconds. After 24 hours, rats were given 0.1mg/kg MK-801 or saline 30 minutes before injection of saline or test compound (dose (). 1-2.5 mg/kg, i.p.), which was 30 minutes before the start of the test. The rat is again placed in the illuminated compartment with the gate open. The waiting time to enter the darkened compartment was recorded for up to 180 seconds, at which point the test was terminated.

All data were analyzed by analysis of variance (ANOVA), and individual comparisons were performed using the Kewman-Keuls test. On average, nude mice took less than 30 seconds to cross the illuminated compartment into the dark compartment. However, most of the vehicle-pretreated rats no longer entered the dark compartment after 24 hours of shock exposure; the average wait time was increased to 175 seconds (p < 0.001). Pretreatment with MK-801(0.1mg/kg) significantly reduced this waiting time compared to vehicle (p < 0.001). The actual test compound reversed this amnesic effect of MK-801 in a dose-dependent fashion in a statistically significant manner.

Example 12

Rat radiomaze task, in vivo testing for learning and memory

The experiments were performed as described previously (Zhang, h. -t., Crissman, a.m., Dorairaj, n.r., Chandler, l.j., and O' Donnell, j.m., Neuropsychopharmacology, 2000, 23, 198-. After 5 days of initial cage rearing, rats (male Spraque-Dawley (Harlan) weighing 250-350 g) were placed in an eight-arm radial maze (60X 10X 12cm per arm height; the maze was raised 70cm above the ground) to acclimate for two days. The rats were then placed individually in the center of the maze for 5 minutes and the bolus was placed near the food well, followed by the well at the end of the arm on the next day; the operation was performed twice daily. Then, four randomly selected arms were each baited with a bolus of food. The rat was confined to a central platform (26 cm diameter) for 15 seconds and then allowed to move freely through the maze until it collected all the bolus of food or over 10 minutes, whichever occurred first and whichever was used. Four parameters were recorded: 1) working memory errors, i.e. entry into the bait arm that has been visited during the same trial; 2) referencing a memory error, i.e., entering an arm not baited; 3) a master arm enters; and 4) duration of the test (seconds), i.e. the time it takes to collect all the food mass in the maze. If in 5 consecutive trials the working memory errors were all zero and the mean reference memory error was less than 1, the rats started the drug trial. MK-801 or saline was injected 15 minutes later with vehicle or test drug, and the test was started 45 minutes later. Experiments were performed in a lighted room containing several additional visual cues from the maze.

All data were analyzed by analysis of variance (ANOVA) and individual comparisons were performed using the Kewman-Keuls test. MK-801(0.1mg/kg, i.p.) increased the frequency of working and reference memory errors (p < 0.01) compared to controls. Administration of the actual test compound reverses this amnesic effect of MK-801 on working memory in a dose-dependent fashion in a statistically significant manner.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

While particular compounds and processes of the present invention have been illustrated, it will be apparent that changes and modifications can be made without departing from the spirit or scope of the invention.

Claims

1. A compound of formula I:

wherein,

R¹is cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms;

R²has 1 to 12 carbon atomsUnsubstituted or substituted one or more times by: halogen, hydroxy, cyano, or combinations thereof, wherein one or more-CH₂Each independently of the others, optionally substituted by-O-, -S-or-NH-, and wherein optionally one or more-CH₂CH₂The radicals-are in each case replaced by-CH-or-C.ident.C-,

alkyl ethers having 3 to 12 carbon atoms,

cycloalkylalkyl having 4 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: c_1-4Alkyl, halo C_1～4Alkyl radical, C_1～4-alkoxy, cyano, halogen or combinations thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～ ₄Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4Alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

arylalkyl having from 7 to 16 carbon atoms which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, and,C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof, heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

heteroarylalkyl wherein the heteroaryl moiety has 5 to 10 ring atoms, at least one of which is a heteroatom, and the alkyl moiety has 1 to 3 carbon atoms, said heteroaryl moiety being unsubstituted or substituted one or more times with: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

a heterocycle having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino, carboxy, alkoxycarbonyl or a combination thereof,

heterocycle-alkyl wherein the heterocyclic moiety has 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom and the alkyl moiety has 1 to 3 carbon atoms, said heterocyclic moiety being non-aromatic and unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino, carboxy, alkoxycarbonyl or combinations thereof, or

A carbocycle, which is a non-aromatic monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～ ₄Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof;

with the proviso that:

(a) when R is¹When it is cyclopropyl, R²Is other than 4-methylbenzyl; and is

(b) When R is¹When cyclopropyl is present, then R²Is not cyclopropylmethyl.

2. A compound according to claim 1, wherein R¹Is a cycloalkyl group.

3. A compound according to claim 1, wherein R¹Is a cycloalkylalkyl group.

4. A compound according to claim 1, wherein R²Is an alkyl group.

5. A compound according to claim 1, wherein R²Is an alkyl ether.

6. A compound according to claim 1, wherein R²Is a cycloalkyl group.

7. A compound according to claim 1, wherein R²Is an aryl group.

8. A compound according to claim 1, wherein R²Is an arylalkyl group.

9. A compound according to claim 1, wherein R²Is heteroaryl.

10. A compound according to claim 1, wherein R²Is heteroarylalkyl.

11. A compound according to claim 1, wherein R²Is a heterocyclic ring.

12. A compound according to claim 1, wherein R²Heterocycle-alkyl.

13. A compound according to claim 1, wherein R²Is carbocyclic.

14. A compound according to claim 1, wherein R¹Is cycloalkyl or cycloalkylalkyl.

15. A compound according to claim 4, wherein R¹Is cycloalkyl or cycloalkylalkyl.

16. A compound according to claim 5, wherein R¹Is cycloalkyl or cycloalkylalkyl.

17. A compound according to claim 6, wherein R¹Is cycloalkyl or cycloalkylalkyl.

18. A compound according to claim 7, wherein R¹Is cycloalkyl or cycloalkylalkyl.

19. A compound according to claim 8, wherein R¹Is cycloalkyl or cycloalkylalkyl.

20. A compound according to claim 9, wherein R¹Is cycloalkyl or cycloalkylalkyl.

21. A compound according to claim 10, wherein R¹Is cycloalkyl or cycloalkylalkyl.

22. A compound according to claim 11, wherein R¹Is cycloalkyl or cycloalkylalkyl.

23. A compound according to claim 12, wherein R¹Is cycloalkyl or cycloalkylalkyl.

24. A compound according to claim 13, wherein R¹Is cycloalkyl or cycloalkylalkyl.

25. A compound according to claim 1, wherein R¹Is cyclopropyl, cyclopentyl or cyclopropylmethyl.

26. A compound according to claim 1, wherein R¹Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

27. A compound according to claim 1, wherein R¹Is cyclopropyl.

28. A compound according to claim 1, wherein R²Is alkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl or alkyl ether.

29. A compound according to claim 1, wherein R²Is ethyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl or arylalkyl, which is unsubstituted or substituted one or more times by: F. cl, CN, CF₃、CH₃、C₂H₅Isopropyl, OCH₃Methylenedioxy, ethylenedioxy, or combinations thereof.

30. A compound according to claim 1, wherein R²Is a substituted or unsubstituted benzyl, phenethyl or phenylpropyl group.

31. The compound according to claim 1, wherein the compound is selected from the group consisting of:

6-cyclopropylamino-9- (2-fluorobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-fluorobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2, 6-difluorobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2, 3-difluorobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9-propyl-2-trifluoromethylpurine

6-cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine

6-cyclopropylamino-9- (3, 4-dimethoxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3, 4-methylenedioxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-thienylmethyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2-methylphenylethyl) -2-trifluoromethylpurine

6-cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine

6-cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine

6-cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine

6-cyclopropylamino-9-phenyl-2-trifluoromethylpurine

6-cyclopropylamino-9- (2-fluorophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine

6-Cyclopropylamino-9- (2-norbornane) -2-trifluoromethylpurine

6-cyclopropylamino-9- (1-indanyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-fluorophenyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (4-chlorophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-thienyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-cyclopentyloxy-4-methoxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2, 6-dichloro-4-pyridylmethyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-methoxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-methoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-methoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2-methoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-cyanophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2, 4-dimethoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-nitrobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (6-methoxy-3-pyridyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-pyridyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-pyridyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-dimethylaminophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-aminophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-furyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-ethoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2-ethoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3, 4-methylenedioxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-ethoxyphenyl) -2-trifluoromethylpurine; and

their pharmaceutically acceptable salts.

32. The compound according to claim 31, wherein said compound is selected from the group consisting of:

6-cyclopropylamino-9- (2, 3-difluorobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine

6-cyclopropylamino-9- (3, 4-dimethoxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine

6-methylamino-9-cyclopentyl-2-trifluoromethylpurine

6-cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine

6-methylamino-9-cycloheptyl-2-trifluoromethylpurine

6-cyclopropylamino-9-phenyl-2-trifluoromethylpurine

6-cyclopropylamino-9- (2-fluorophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine

6-Cyclopropylamino-9- (2-norbornane) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-fluorophenyl) -2-trifluoromethylpurine

6-Cyclopropylamino-9- (4-chlorophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-thienyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2, 6-dichloro-4-pyridylmethyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-methoxybenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-methoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-methoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (2-methoxyphenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-cyanophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-nitrobenzyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (4-pyridyl) -2-trifluoromethylpurine

6-methylamino-9- (2, 4-dimethoxy-5-pyrimidinyl) -2-trifluoromethylpurine

6-methylamino-9- (4-methoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-acetylphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-methoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine

6-cyclopropylamino-9- (3-ethoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine;

and pharmaceutically acceptable salts thereof.

33. A compound according to claim 1, wherein R²Is a cycloalkylalkyl group.

34. A compound according to claim 33, wherein R¹Is cycloalkyl or cycloalkylalkyl.

35. A compound of formula I and pharmaceutically acceptable salts thereof,

wherein

R¹Is methyl, ethyl or cyclopropyl; and is

R²Is cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4Alkyl radical, C_1～4-alkoxy, cyano or a combination thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～ ₄Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group, a phenoxy group, or a combination thereof,

heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof,

a heterocycle having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1～4-alkylamino, di-C_1～4-alkylamino, carboxy, alkoxycarbonyl or combinations thereof, or

A carbocycle, which is a non-aromatic monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4Alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～ ₄Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof.

36. The compound according to claim 35, wherein said compound is selected from the group consisting of:

6-methylamino-9-cyclopentyl-2-trifluoromethylpurine

6-methylamino-9-cycloheptyl-2-trifluoromethylpurine

6-methylamino-9- (2, 4-dimethoxy-5-pyrimidinyl) -2-trifluoromethylpurine

6-methylamino-9- (2-methoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (4-methoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-acetylphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-methoxyphenyl) -2-trifluoromethylpurine

6-methylamino-9- (3-nitrophenyl) -2-trifluoromethylpurine

6-methylamino-9- (3, 4-dimethoxyphenyl) -2-trifluoromethylpurine; and

their pharmaceutically acceptable salts.

37. A compound of formula I and pharmaceutically acceptable salts thereof,

wherein

R¹Is methyl, ethyl or cyclopropyl; and is

R²Is a phenyl group, and the phenyl group,

phenyl substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～ ₄-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxy alkoxy, carboxy, cyano, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof, or

Heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl radical, C_1～ ₄Alkoxy, cyano, trifluoromethyl, nitro, amino, C_1～4-alkylamino, di-C_1～4-an alkylamino group or a combination thereof,

or when R is¹When it is methyl or cyclopropyl, R²The cycloalkyl group may have 3 to 12 carbon atoms.

38. A compound of formula I:

wherein,

R¹is a compound of formula (I) in the formula (H),

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms;

A carbocycle, which is a non-aromatic monocyclic or bicyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～ ₄Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4Alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof;

with the proviso that when R¹When it is H, then R²Not a substituted tetrahydrofuranyl group.

39. A compound according to claim 38, wherein R¹Is alkyl, cycloalkyl or cycloalkylalkyl.

40. Use of a compound according to any one of claims 1 to 39 for the manufacture of a medicament for improving cognition in a patient.

41. The use according to claim 40, wherein the compound is administered in an amount of 0.01 to 100mg/kg body weight/day.

42. Use of a compound according to any one of claims 1 to 39 for the manufacture of a medicament for treating a patient suffering from cognitive impairment or decline.

43. The use according to claim 42, wherein the patient suffers from a memory disorder.

44. The use according to claim 42, wherein the compound is administered in an amount of 0.01 to 100mg/kg body weight/day.

45. The use according to claim 42, wherein the patient is suffering from memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, brain aging, multi-infarct dementia, HIV or cardiovascular disease.

46. Use of a compound according to any one of claims 1-39 for the preparation of a medicament for treating a patient suffering from a disease involving reduced cAMP levels.

47. Use of a compound of any one of claims 1-39 for the manufacture of a medicament for inhibiting PDE4 enzyme activity in a patient.

48. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

49. The composition according to claim 48, wherein said composition comprises 0.1 to 50mg of said compound.

50. Use of a compound according to any one of claims 1 to 39 for the preparation of a medicament for the treatment of a patient suffering from memory impairment as a result of a neurodegenerative disease.

51. The use of a compound according to any one of claims 1 to 39 for the preparation of a medicament for the treatment of a patient suffering from memory impairment as a result of an acute neurodegenerative disease.

52. Use of a compound according to any one of claims 1 to 39 for the preparation of a medicament for the treatment of a patient suffering from an allergic or inflammatory disease.

53. A process for the preparation of a compound according to claim 1,

wherein

R¹Is a compound of formula (I) in the formula (H),

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms; and is

R²Aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4-hydroxyalkoxy, carboxyl, cyano,Hydroxamic acid, formamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof, or

Heteroaryl having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, which is unsubstituted or substituted one or more times by: halogen, aryl, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, cyano, trifluoromethyl, nitro, amino, C_1～4-alkylamino, di-C_1～4Alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-an alkylsulfonyl group or a combination thereof;

the method comprises the following steps:

reacting 6-N-R in the presence of a trialkylamine compound having 1 to 5 carbon atoms per alkyl group as a base, a copper catalyst, and a polar aprotic solvent at a temperature of at least 50 ℃¹-2-CF₃Substituted adenine is reacted with an arylboronic acid or a heteroarylboronic acid.

54. The method according to claim 53, wherein the trialkylamine is triethylamine.

55. The method according to claim 53, wherein said polar aprotic solvent is THF or CH₃CN。

56. The method according to claim 55, wherein said polar aprotic solvent is CH₃CN。

57. The process according to claim 53, wherein the reaction is carried out at a temperature of 50-60 ℃.

58. A process for the preparation of a compound according to claim 35,

wherein

R¹Is methyl, ethyl or cyclopropyl, and

R²aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by: halogen, C_1～4Alkyl, halo C_1～4-alkyl, hydroxy, C_1～4-alkoxy, halo C_1～4Alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1～4-alkylamino, di-C_1～4-alkylamino radical, C_1～4-hydroxyalkyl, C_1～4Hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2～4-acyl group, C_2～4-alkoxycarbonyl, C_1～4Alkylthio radical, C_1～4-alkylsulfinyl, C_1～4-alkylsulfonyl, phenoxy or combinations thereof, or

the method comprises the following steps:

59. A process for the preparation of a compound according to claim 38,

wherein

R¹Is a compound of formula (I) in the formula (H),

cycloalkyl having 3 to 6 carbon atoms, or

Cycloalkylalkyl having 4 to 7 carbon atoms; and is

the method comprises the following steps:

60. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

61. A pharmaceutical composition comprising a compound of claim 37 and a pharmaceutically acceptable carrier.

62. A pharmaceutical composition comprising a compound of claim 38 and a pharmaceutically acceptable carrier.